Consumption of alcohol during pregnancy can have devastating effects on the fetus, ranging from prenatal mortality to physical and behavioral anomalies. Important research questions include the identification of risk factors that contribute to the increased likelihood of fetal alcohol effects, the elucidation of the mechanisms by which alcohol causes brain damage and consequent behavioral alterations, and the development of effective intervention and treatment strategies. We propose to use an animal model system of human third trimester exposure to study these questions. There is a large variability of outcomes following exposure to alcohol, even when similar amounts of alcohol are consumed. One factor that has been proposed to account for this variability is a difference in genetically determined sensitivity to alcohol. The selectively bred HAS and LAS rat lines were selected for extremes in ethanol sensitivity. Using these lines we will investigate the contribution of ethanol sensitivity on three behavioral measures affected by alcohol exposure: activity, coordination, and reversal learning. We will also assess cell loss in the hippocampus and cerebellum, two brain areas especially affected by perinatal alcohol exposure in an attempt to correlate behavioral deficits with underlying anatomical changes. A second line of investigation will investigate the role of ethanol withdrawal on fetal alcohol effects, since physiological changes that occur during withdrawal might have an impact on the developing fetus. The effects of gradual withdrawal from ethanol will be compared to abrupt withdrawal to provide additional evidence that withdrawal-induced excitotoxicity plays a role in fetal alcohol effects. Other studies will examine the mechanisms by which this excitotoxicity may operate. In particular, the effects of specific antagonists of the NMDA receptor complex and the cascade of events that occur following activation of this receptor will be studied to help determine the mechanism(s) by which perinatal withdrawal might influence fetal development.